alatrofloxacin and trovafloxacin

The new fourth-generation fluoroquinolone, trovafloxacin, is active in vitro against gram-positive and gram-negative organisms, atypical pathogens, and anaerobes, and has pharmacokinetics permitting once-daily intravenous or oral dosing. Safety/tolerability data from phase II/III clinical trials of sequential intravenous alatrofloxacin to oral trovafloxacin and single-dose intravenous or oral prophylaxis are summarized.. All trials were double-blind, randomized, and multicenter. In multidose trials with alatrofloxacin, 1,257 patients requiring initial intravenous therapy received once-daily alatrofloxacin (trovafloxacin prodrug, 200 or 300 mg/day) followed by oral 200 mg/day trovafloxacin. An additional 444 patients received a single alatrofloxacin or trovafloxacin dose prophylactically for surgical procedures.. Therapy with alatrofloxacin was well tolerated. The most common treatment-related adverse events in studies of intravenous alatrofloxacin followed by oral trovafloxacin were nausea, headache, insertion site reaction, and dizziness. In single-dose intravenous or oral prophylaxis studies, insertion-site reaction, pruritus, and insertion-site pain were the most common treatment-related adverse events. No serious quinolone toxicity or drug interactions were reported. The incidence of serious treatment-related adverse events was < 1% in both the alatrofloxacin and comparator groups. In comparative trials, mortality due to all causes after trovafloxacin was similar to that after comparative agents; there was no mortality related to trovafloxacin administration.. In this large patient sample, intravenous alatrofloxacin followed by oral trovafloxacin was safe and well tolerated. Serious adverse events, such as phototoxicity, cardiovascular toxicity, and hemolytic anemia associated with older fluoroquinolones, were not noted with trovafloxacin. No interactions of trovafloxacin with other drugs were reported. The safety and tolerability of trovafloxacin, along with in vitro activity against key pathogens and pharmacokinetics permitting once-daily administration, support its oral and intravenous use in patients with obstetric, gynecologic, and intra-abdominal infections as well as for prophylaxis of surgical infection.

Topics: Administration, Oral; Adult; Aged; Anti-Infective Agents; Antibiotic Prophylaxis; Bacterial Infections; Drug Administration Schedule; Drug Interactions; Female; Fluoroquinolones; Humans; Infusions, Intravenous; Male; Middle Aged; Naphthyridines; Prodrugs; Surgical Wound Infection

IV/PO moxifloxacin was evaluated in the treatment of hospitalized patients with severe community-acquired pneumonia (CAP).. Data were pooled from two prospective, randomized studies. In the multinational study, patients received 7-14 days IV/PO moxifloxacin 400 mg QD or IV/ PO amoxicillin clavulanate 1200/625 mg TID +/- IV/PO clarithromycin 500 mg BID. In the North American study, patients received 7-14 days IV/PO moxifloxacin 400 mg QD, IV/ PO alatrofloxacin/trovafloxacin 200 mg QD, or IV/PO levofloxacin 500 mg QD. The primary endpoint was clinical success at the test-to-cure visit. Severe CAP was defined according to the 1993 ATS criteria.. In the clinically valid population, clinical success rates were 88% (167/190) for moxifloxacin- and 83% (155/186) for comparator-treated patients (95% CI = -1.9%, 12.2%). Corresponding clinical success rates for the microbiologically valid population were 87% (59/68) and 84% (54/64), respectively (95% CI = 8.6%, 15.0%). A switch from IV to PO therapy was made by day 5 of therapy for 73% of moxifloxacin- vs. 60% of comparator-treated patients (P < 0.01). Clinical success rates were similar in a retrospective analysis using the revised 2001 ATS definition of severe CAP. Mortality rates were 6% (15/241) and 10% (24/238) in the moxifloxacin and comparator treatment groups, respectively. The incidence of drug-related adverse events was similar in both treatment groups.. Sequential IV/PO moxifloxacin 400 mg QD is as safe and effective as other fluoroquinolones and a beta-lactam/macrolide combination for treating hospitalized patients with severe CAP.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aza Compounds; Clarithromycin; Community-Acquired Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Male; Middle Aged; Moxifloxacin; Naphthyridines; Pneumonia, Bacterial; Quinolines; Retrospective Studies; Treatment Outcome

The pharmacokinetics of trovafloxacin following administration of a single intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children (ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to trovafloxacin, with an average +/- standard deviation (SD) peak trovafloxacin concentration determined at the end of the infusion of 4.3 +/- 1.4 microg/ml. The primary pharmacokinetic parameters (average +/- SD) analyzed were volume of distribution at steady state (1.6 +/- 0.6 liters/kg), clearance (151 +/- 82 ml/h/kg), and half-life (9.8 +/- 2.9 h). The drug was well tolerated by all children. There were no age-related differences in any of the pharmacokinetic parameters studied. Less than 5% of the administered dose was excreted in the urine over 24 h. On the basis of the mean area under the concentration-time curve of 30.5 +/- 10.1 microg. h/ml and the susceptibility (< or =0.5 microg/ml) of common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once or twice daily should be appropriate.

Topics: Adolescent; Anti-Infective Agents; Bacterial Infections; Child; Child, Preschool; Drug Interactions; Fluoroquinolones; Humans; Infant; Injections, Intravenous; Metabolic Clearance Rate; Naphthyridines; Prodrugs

Trovafloxacin pharmacokinetics were evaluated in 12 subjects with AIDS. By using a randomized design, single 200-mg doses of oral trovafloxacin and intravenous alatrofloxacin were administered. The mean absolute bioavailability was 91%. The pharmacokinetics of trovafloxacin when administered orally as the active form or intravenously as the prodrug (alatrofloxacin) are not altered in subjects with AIDS compared to those in healthy adults.

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Anti-Infective Agents; Area Under Curve; Biological Availability; Cross-Over Studies; Fluoroquinolones; Half-Life; Humans; Injections, Intravenous; Naphthyridines; Prodrugs; Sample Size

A simplified dosing algorithm for trovafloxacin was evaluated following a single-dose infusion of alatrofloxacin at trovafloxacin equivalent doses of 30, 100, 200, 300 and 400 mg (57 subjects), and multiple doses of 200, 300 and 400 mg (30 subjects). Maximum serum concentration and area under the concentration-time curve for trovafloxacin increased with dose. Trovafloxacin clearance (82-85 ml x h/kg) and volume of distribution (1.3-1.6 l/kg) were independent of dose. Infusion of alatrofloxacin at a trovafloxacin equivalent dose of 300 mg at 1, 2 or 3 mg/ml over 1 h did not alter the pharmacokinetics of trovafloxacin. A plot of the weight-adjusted dose of trovafloxacin in individual subjects against the maximum serum concentration following single and multiple dosing, indicated that the maximum serum concentration increased 1 microg/ml for each 1 mg/kg of trovafloxacin administered. Thus, a prior knowledge of the desired serum concentration will permit appropriate dosing without the use of complex nomograms in patients with normal hepatic function.

Topics: Administration, Oral; Adolescent; Adult; Anti-Infective Agents; Drug Administration Schedule; Fluoroquinolones; Half-Life; Humans; Infusions, Intravenous; Male; Middle Aged; Naphthyridines; Prodrugs

Fifteen healthy male volunteers (in four groups) received single 1 h i.v. infusions of alatrofloxacin (CP-116,517) equivalent to 30, 100, 200 or 300 mg of its active metabolite, trovafloxacin (CP-99,219). Blood and urine were sampled over 73 and 72 h, respectively, and plasma levels of alatrofloxacin and serum concentrations of trovafloxacin were determined by HPLC with UV detection. Alatrofloxacin was not detectable in plasma samples collected after the end of infusion, indicating rapid conversion to trovafloxacin. Maximum serum concentrations of trovafloxacin were achieved at the end of the infusions. Mean maximum plasma trovafloxacin concentrations for the four alatrofloxacin doses were 0.4, 1.8, 2.3 and 4.3 mg/L. The mean area under the concentration-time curve increased proportionally with the dose. The elimination half-life (T(1/2)) for trovafloxacin was independent of the dose and the mean T(1/2)s for the 100, 200 and 300 mg equivalent doses of alatrofloxacin were 10.4, 12.3 and 10.8 h. Approximately 10% of the equivalent dose was recovered as unchanged trovafloxacin in the urine. No clinical adverse or laboratory reactions were associated with i.v. administration of alatrofloxacin and its conversion to trovafloxacin. These results indicate that alatrofloxacin is rapidly converted to trovafloxacin and that the pharmacokinetic parameters for this new fluoroquinolone after i.v. administration of its parent compound are similar to those reported after oral administration of equivalent trovafloxacin doses.

Topics: Adult; Anti-Infective Agents; Area Under Curve; Chromatography, High Pressure Liquid; Double-Blind Method; Fluoroquinolones; Half-Life; Humans; Infusions, Intravenous; Male; Naphthyridines; Prodrugs

Two studies determined the oral bioavailability of trovafloxacin (CP-99,219) in healthy volunteers under fasted and fed conditions. In a randomized, two-way crossover study, 12 fasting subjects received two 100 mg tablets of trovafloxacin and an equivalent dose of alatrofloxacin (CP-116,517), administered by i.v. infusion over 1 h. Alatrofloxacin, the L-Ala-L-Ala prodrug of trovafloxacin, is rapidly converted in the body to trovafloxacin. After the oral dose of trovafloxacin, the mean Cmax and AUC were 2.2 mg/L and 30.4 mg x h/L, respectively. After the infusion of alatrofloxacin, the Cmax and AUC of trovafloxacin were 3.2 mg/L and 34.7 mg x h/L, respectively. The mean T(1/2) after both treatments was about 11 h. The mean Cl and Vd(ss) of trovafloxacin after the infusion of alatrofloxacin were 1.32 mL/min/kg and 1.13 L/kg, respectively. The mean oral bioavailability of trovafloxacin was estimated to be 87.6% (range 64.8-122.1%). Another randomized, open, three-way crossover study was conducted in 12 healthy male volunteers to investigate the effect of food in the gastrointestinal tract on the bioavailability of trovafloxacin. Each subject received three 100 mg tablets after fasting overnight (treatment A) or after a standard breakfast (treatment B), or 300 mg as oral aqueous suspension after fasting overnight (treatment C). Mean Tmax after treatment B occurred 2.2 h later (3.6 h vs 1.4 h) than after treatment A. Mean Cmax and AUC were 2.3 and 2.6 mg/L and 38.2 and 39.5 mg x h/L after B and A, respectively. About 5% of the administered dose was recovered unchanged in the 24 h urine sample after all three treatments. Thus, the food reduced mean Cmax by 12% but had no appreciable effect on mean AUC. The mean bioavailability of trovafloxacin administered as treatment regimen B was 96.6% relative to that of treatment A. The respective mean bioavailabilities of trovafloxacin as treatments B and A were 91.3% and 94.5% respectively of that of treatment C. The results of these studies indicate that trovafloxacin has good oral bioavailability and that the ingestion of food is unlikely to have a clinically significant effect on the bioavailability of trovafloxacin.

Topics: Administration, Oral; Adult; Anti-Infective Agents; Biological Availability; Fasting; Female; Fluoroquinolones; Humans; Infusions, Intravenous; Male; Naphthyridines; Prodrugs

Alatrofloxacin functions similar to other fluoroquinolone antibiotics in that it not only has antibiotic activity to kill invading organisms by interfering with DNA synthesis, it possesses immunosuppressive activity. In the first hour after bacteria have been phagocytosed by THP-1 monocytes, the drug activates a lytic mechanism involving the release of c-AMP, tumor necrosis factor (TNFalpha), interleukin-1 (IL-1), IL-6 and nitric oxide, with elevations in lysosomal hydrolytic enzyme activities. This effect reverses between 2 and 4 h. At this time, all of these inflammatory processes are returned to normal values or below suggesting that alatrofloxacin reduces the spread of infection and destruction of tissue related to inflammation.

Topics: Adjuvants, Immunologic; Anti-Inflammatory Agents; Cell Line; Cytokines; Fluoroquinolones; Humans; Monocytes; Naphthyridines; Phagocytosis; Prodrugs; Staphylococcus aureus; Superoxide Dismutase; Time Factors

Topics: Anti-Infective Agents; Drug and Narcotic Control; European Union; Fluoroquinolones; Humans; Naphthyridines

Trovafloxacin is a new fourth-generation fluoroquinolone whose pharmacokinetics and in vitro activity suggest that it is well suited for antibiotic prophylaxis in elective colorectal surgery. Alatrofloxacin is a prodrug that is rapidly hydrolyzed to trovafloxacin in the body.. Twelve patients received a single dose of alatrofloxacin equivalent to 200 mg trovafloxacin by intravenous infusion over 1 hour. Surgery was started at various time points relative to infusion time to allow determination of trovafloxacin concentrations in serum, colonic tissue, and peritoneal fluid as a function of time.. The concentration in the earliest colonic tissue sample (1.4 hours after dosing) was 1.4 microg/g. The maximum colonic tissue concentration was 2.8 microg/g in a sample taken 2 hours after dosing. Colonic tissue/serum concentration ratios in samples taken 2-10 hours after the end of infusion ranged from 0.8 to 1.47. Concentrations of trovafloxacin in peritoneal fluid ranged from below the level of quantitation to 2.1 microg/mL at the time of colonic tissue sampling and from below the level of quantitation to 2.5 microg/mL at the time of wound closure. Alatrofloxacin was well tolerated.. After a single intravenous dose of alatrofloxacin equivalent to 200 mg trovafloxacin, trovafloxacin is distributed rapidly into colonic tissue and peritoneal fluids. Tissue concentrations approximate serum concentrations and decline in parallel for up to 10 hours after dosing.

Topics: Adult; Aged; Anti-Infective Agents; Antibiotic Prophylaxis; Ascitic Fluid; Colon; Female; Fluoroquinolones; Humans; Infusions, Intravenous; Male; Middle Aged; Naphthyridines; Prodrugs; Rectum

A single-dose study was conducted to determine concentrations of trovafloxacin (CP-99,219) achieved in the cerebrospinal fluid (CSF) relative to those in the serum of healthy subjects after intravenous infusion of alatrofloxacin (CP-116,517), the alanyl-alanyl prodrug of trovafloxacin. Twelve healthy subjects were administered single doses of alatrofloxacin at a trovafloxacin equivalent of 300 mg as an intravenous infusion over 1.0 h. CSF samples were taken by lumbar puncture at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 24 h after the start of the infusion; each subject was sampled at only one time point. Serum samples were taken from each subject at the time of CSF collection. A mean concentration of 5.8 microg of trovafloxacin per ml was present in serum 1.0 h after the start of the infusion. CSF/serum ratios ranged from 0.14 to 0.33 in the postdistribution phase (5 to 24 h postinfusion), with a mean ratio of 0.25. The most common adverse events were dizziness, nausea, and rash and were mild or moderate in intensity. The potency of trovafloxacin against susceptible organisms, coupled with its rapid penetration of CSF following the intravenous administration of alatrofloxacin, suggests that it may be useful in the treatment of bacterial meningitis in humans.

Topics: Adolescent; Adult; Anti-Infective Agents; Drug Administration Schedule; Female; Fluoroquinolones; Humans; Infusions, Intravenous; Male; Middle Aged; Naphthyridines; Prodrugs